The overall goal of this PPG is to evaluate the hypothesis that calpain inhibition represents a viable therapeutic target for intervention following traumatic brain injury (TBI). TBI represents a leading cause of death and disability in adults and children, and improved treatment options are urgently needed. Calpains are excessively activated following TBI and are strongly implicated in the secondary neuronal degeneration. The resultant hypothesis is that calpain inhibition will protect against the pathological and functional consequences of TBI. Although straightforward, this hypothesis has proven to be surprisingly difficult to evaluate. A handful of studies in animal models of TBI have demonstrated improved neurological recovery and attenuated axonal injury with calpain inhibitor treatment. However, evidence that these benefits are directly related to calpain inhibition has been elusive. Moreover, there are numerous unanswered questions regarding the mechanisms by which calpains contribute to cell death and dysfunction. This PPG brings together investigators with strong expertise in calpain biochemistry and in animal models of TBI to evaluate three distinct mechanisms of calpain inhibition following TBI. Project 1 explores the role of the endogenous, specific, and potent calpain inhibitor, calpastatin, in modulating calpain function and improving outcome following TBI. Project 2 is translational and will investigate the ability of new small molecule calpain inhibitors to attenuate the pathological and functional consequences of TBI. Project 3 will examine the roles of individual calpain isoforms in neurodegeneration and TBI, focusing on the hypothesis that u-calpain is a pathologic isoform and is localized to mitochondria. In addition to the three projects, there will be three cores: A, Administrative and Biostatistical Core;B, Animal Core;and C, Proteomics and Biomarker Core. Together, these projects and cores will provide a clear indication as to whether calpain inhibition represents a viable therapeutic target for TBI, and whether the small molecule calpain inhibitors are suitable for subsequent preclinical and clinical investigation.